Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle–Ottawa scale (cohort studies). We included 11 studies (n = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = −0.71 (95% confidence interval (CI) −1.32 to −0.10), P = 0.02, I2 = 51%] and QoL [SMD = 0.88 (95% CI 0.30–1.45), P = 0.003, I2 = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = −0.95 (95% CI −1.45 to −0.45, P < 0.001, I2 = 11%], anxiety [SMD = −0.92 (95% CI 1.72 to −0.13), P = 0.023, I2 = 65%] and QoL [SMD = 1.14 (95% CI 0.66–1.62), P < 0.001, I2 = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.


Introduction
Inflammatory bowel disease (IBD) is a debilitating, relapsing-remitting illness, which primarily comprises ulcerative colitis and Crohn's disease.IBD is associated with unpredictable, painful and often disabling symptoms for patients [1].Rates of depression are over twice as high in individuals with IBD than in the general population, and these rates are significantly higher for those with active IBD compared to inactive IBD [2].Notably, the comorbidity of depression is associated with poor IBD outcomes, including increased risk of IBD relapse, hospitalisation, requirement for biologic therapy and surgery [3].This suggests that effective treatment of depression could improve both quality of life and IBD outcomes.
Antidepressants are an effective treatment for patients with depression and anxiety in the general population and are also commonly used to treat psychological comorbidities in patients with IBD [4].The comorbidity of IBD, however, poses potential barriers to effectiveness and tolerability of antidepressants.These challenges include the burden of IBD symptoms (e.g.pain and diarrhoea), impaired drug absorption [5], and possible increased vulnerability to side-effects in this population [4].A systematic review of antidepressants in IBD from 2017 was limited by lack of available trials and lack of data on adverse events [6].A recent meta-analysis found antidepressants to be effective in patients with IBD.The findings of this synthesis, however, were based primarily on studies where randomisation or blinding procedures were not reported [7], thereby seriously undermining the validity of the findings.Furthermore, the authors did not analyse by antidepressant class, meaning it remains unclear which specific antidepressants are likely to be most beneficial in patients with IBD.
We therefore performed an updated systematic review and meta-analysis of the effect of antidepressants in patients with IBD, in which we only meta-analysed randomized controlled trials (RCTs).We hypothesized that antidepressants would improve depressive symptoms, anxiety symptoms and quality of life in IBD.
which studies that meet review criteria are examined and RCTs and with sufficient data pooled for meta-analysis.

Study selection
We included studies that met all the following criteria: (a) recruited participants clinically diagnosed with any type of IBD (Crohn's disease, ulcerative colitis or indeterminate colitis); (b) were RCTs, non-RCTs, case-control studies, prospective and retrospective observational studies, case series or case reports; (c) participants were prescribed any of the following antidepressants at the start of the research: a selective serotonin reuptake inhibitor (SSRI) (sertraline, fluoxetine, paroxetine, fluvoxamine, citalopram, escitalopram), tricyclic antidepressant (amitriptyline, nortriptyline, imipramine, clomipramine, desipramine), tetracyclic antidepressant (mirtazapine, mianserin), serotonin and noradrenaline reuptake inhibitor (SNRI) (venlafaxine, duloxetine), monoamine oxidase inhibitor (moclobemide, phenelzine, selegiline) or other antidepressant (bupropion, vortioxetine, vilazodone, trazodone) and (d) depression was assessed before and after treatment.Studies were excluded if they met the following criteria: (a) study was qualitative only; (b) study recruited a paediatric population (<18 years) and (c) study was a review article presenting no original data.

Study extraction
We systematically searched PubMed, Cochrane Library Trials, Embase (via Ovid) and Web of Science for studies published from inception to 31 December 2023.The full search strategy is included as supplementary material, Supplemental digital content 1, http://links.lww.com/EJGH/B20.To identify unpublished or ongoing studies, we searched trial registries including ClinicalTrials.govand the European Union (EU) clinical trials register.A manual search of references was carried out on the included studies and four reviews in the area of antidepressant use in IBD.
Two authors (F.W. and C.D.M.) independently performed the literature search and resolved differences over inclusion through discussions and consensus.Two reviewers independently screened titles and abstracts for potentially eligible studies and assessed them for inclusion.
From abstracts fulfilling inclusion criteria, full-text articles were reviewed, and data extraction performed for studies still meeting inclusion criteria.

Data extraction
For each study, we extracted the following data: author, year, country, study design, patient age and sex distribution, IBD type, IBD duration, baseline IBD activity [faecal calprotectin, validated disease indices such as the Crohn's Disease Activity Index (CDAI), serum C-reactive protein], baseline depression and anxiety status, antidepressant treatment (medication, dose, duration of treatment), depression and anxiety after treatment, changes in IBD symptoms or disease activity scores, and frequency of incident adverse effects.

Risk of bias assessment
Due to the various study designs, two quality assessment methods were used.For RCTs and non-RCTs, we used the Cochrane Common Mental Disorders Depression Anxiety and Neurosis group (CCDAN) tool, as it has been specifically designed to assess trials related to depressive disorders [9].The CCDAN consists of 23 items, and gives a score out of 46, with a score of 20 or more suggesting high quality.For cohort studies, the Newcastle-Ottawa scale (NOS) was used, which gives studies a score out of 8, with a higher score signifying lower risk of bias [10].

Outcomes
The primary outcome was any validated measure of depressive symptoms at the latest time-point within the study.Secondary outcomes were anxiety symptoms, quality of life (QoL), IBD disease activity and adverse events using any validated instrument.

Measures of effect
For each study, effect size estimates were calculated using the standardized mean difference (SMD) in depressive symptoms after treatment.Where not provided directly, the standard error of each group sizes was estimated [11].

Statistical analysis
We considered pooling with a minimum of three RCTs that were clinically homogeneous.Studies were weighted using an inverse-variance method, where studies with larger precision are afforded greater weight.Pooled effect estimates were calculated using a random-effects model [12].Analyses were performed using STATA 17.0.

Heterogeneity
Heterogeneity between studies was quantified by calculating the I 2 -statistic, I 2 between 25, 50 and 75% suggesting low, moderate and high heterogeneity, respectively [13].Moderate and high heterogeneity were explored using subgroup analysis by antidepressant class.We did not assess for publication bias due to the small number of studies in the meta-analyses.

Results
A total of 4311 studies were retrieved and screened for relevance, of which 4282 papers were excluded at title/ abstract stage and 29 assessed for eligibility.Following full-text review, 11 studies were included (Fig. 1).Table 1 shows the characteristics of included studies.

Randomized controlled trials
Three small placebo-controlled RCT's were included.One used the SSRI fluoxetine for 12 months in 26 patients with Crohn's disease in remission (but with a flare in the last year) [14]; one used the SNRI duloxetine for 6 months in patients with Crohn's disease or ulcerative colitis in remission [15]; and the other used the SNRI venlafaxine for 6 months in 45 patients with ulcerative colitis or Crohn's disease, which also included patients with active IBD [16].For the duloxetine and fluoxetine studies, depression was not an inclusion criterion.For the venlafaxine study, participants required a score ≥8 on the Hospital Anxiety and Depression Scale (HADS), indicative of mild anxiety or depressive symptoms, though did not require a clinical diagnosis of depression.
Following treatment, the duloxetine and venlafaxine trials reported improvement in depression and anxiety scores compared to placebo.There was no significant change in depression or anxiety when using fluoxetine, though baseline depressive symptoms were low and depressive symptoms were a secondary outcome.For IBD control, the venlafaxine study found a significant decrease in both Mayo score and CDAI score after 6 months.The fluoxetine and control CDAI scores and faecal calprotectin levels were comparable at 12 months (Table 2).

Risk of bias
Risk of bias for the studies is shown in Tables 3 and 4. The CCDAN found that the three RCTs were all at low risk of bias [14][15][16], as was the nonrandomized trial of bupropion [17].The nonrandomized trial of tianeptine, however, was at high risk of bias [18].The NOS showed that both cohort studies were at low risk of bias [19,20].

Nonrandomized or open-label trials
In a nonrandomized controlled trial, 60 participants with ulcerative colitis in remission were included and allocated equally to tianeptine -an atypical antidepressant -or placebo [18].After 12 months, those allocated to tianeptine had a significantly improved anxiety symptoms, depressive symptoms and IBD control compared to placebo.In an open-label trial, bupropion -a dopamine and noradrenaline reuptake inhibitor -was not found to improve depressive symptoms or anxiety symptoms [17].Participants, however, had already completed a psychological intervention prior to starting, leading to a probable floor effect (Table 2).

Cohort studies
A prospective cohort study found that antidepressantadherent patients had a significantly greater decrease in anxiety, depressive symptoms and QoL scores compared to nonadherent patients [19].A small retrospective cohort study found 12-month improvement in depressive symptoms, anxiety symptoms and daily bowel frequency in patients treated with antidepressants, although attrition was high [20] (Table 2).

Case series and reports
A case series included eight IBD patients with major depressive disorder [21].Patients were prescribed paroxetine -an SSRI -in an open-label design.At 8 weeks, the patients' mean depressive symptoms significantly decreased from baseline.Three case reports were included [22][23][24].In all three cases, the patients exhibited improved mental health symptoms and IBD disease activity (Table 2).

Discussion
In this systematic review of antidepressants in IBD, we found 11 studies of 327 participants, including three good-quality RCTs.From the RCTs, we found that antidepressants improved depressive symptoms and QoL scores, whilst producing trend improvement in anxiety symptoms.When analysing SNRI antidepressants alone, significant benefit was seen for depressive symptoms, anxiety symptoms and QoL.Apart from transient side-effects and an increased incidence of nausea in the duloxetine RCT, tolerability was comparable to placebo.
Although antidepressants are effective in the general population, the comorbidity of IBD poses potential barriers to their use.For example, patients with IBD frequently have active gastrointestinal symptoms, chronic pain, elevated systemic inflammation and can have impaired intestinal absorption [5], emphasising the need for clinical trials of antidepressants specifically in IBD.Whilst a recent meta-analysis found benefit of antidepressants for depression in IBD, its findings were primarily based on studies with a high risk of bias [7]

Features of GAD
Mirtazapine 15 mg at night BDI, Beck depression inventory; CDAI, Crohn's disease activity index; GAD, generalized anxiety disorder; HADS, the hospital anxiety and depression scale; HAD-A, the hospital anxiety and depression scale -anxiety; HAD-D, the hospital anxiety and depression scale -depression; HBI, Harvey-Bradshaw index; HAMA, Hamilton anxiety scale; HARS, Hamilton anxiety rating scale; HAM-A, Hamilton rating scale for anxiety; HAM-D, Hamilton rating scale for depression; HDRS, Hamilton depression rating scale; IBD, inflammatory bowel disease; LCAI, Lichtiger colitis activity index; MMS, modified mayo score; MDD, major depressive disorder; RCT, randomized controlled trial; TNF, tumor necrosis factor.Table 1.Symptoms of depression and anxiety are highly prevalent in IBD, affecting approximately 25 and 32% of patients with IBD, respectively [2].Although these estimates are based on questionnaire scores rather than diagnostic interview, questionnaire-derived depressive symptoms -even at a very low level -are associated with poor IBD outcomes, including increased risk of relapse, hospitalisation and surgery [25].Whilst depression and anxiety symptoms can result from the psychological distress and burden of IBD, depression frequently predates IBD rather than vice versa [26], suggesting a bidirectional relationship.Furthermore, patients with IBD and comorbid irritable bowel syndrome symptoms -around 25% of those in mucosal remission -have worse symptoms of depression and anxiety [27].There is, therefore, likely to be a large IBD subgroup with disordered gut-brain interaction, manifesting with psychological symptoms (e.g.depression and anxiety) and gastrointestinal symptoms (e.g.pain and persistent diarrhoea).
Antidepressants have strong potential in IBD, both for their effects on psychological health and for their potential in reducing disordered gut-brain interaction.Use of antidepressants is associated with lower incidence of IBD, suggesting a possible protective effect on the gut-brain axis [26].SNRIs are effective in improving pain in general [28,29], and it is notable that two of the three successful RCTs used SNRIs, although the low dose of venlafaxine used (150 mg per day) has minimal noradrenergic effects [30].Only one case report tested mirtazapine.This tetracyclic antidepressant enhances serotonin signalling without increasing serotonin concentrations [31].It typically has a neutral effect on gut motility, reduces nausea [32], improves insomnia and has a low risk of sexual dysfunction and gastrointestinal bleeds [33].With only one case report of mirtazapine in IBD to date, our review highlights a need for a trial of mirtazapine in IBD.
Our results also build on a previous systematic review by adding data on adverse events.This is important because side-effects from antidepressants may be more frequently seen in IBD than in the general population [4].SSRIs present challenges in tolerability to patients with IBD compared to the general population, as they can accelerate gut motility, cause/worsen nausea and increase the risk of gastrointestinal bleeding [32,33].Conversely, some SSRIs can have anti-inflammatory effects [34].The SSRI paroxetine, which was used successfully in a small case series in our review, has stronger anticholinergic effects than other SSRIs [35].By improving diarrhoea, this may improve IBD symptoms more than other SSRIs, but the short half-life of paroxetine increases risk of discontinuation syndrome on cessation [33].Bupropion, a noradrenaline and dopamine reuptake  inhibitor, may be particularly promising in IBD because it marginally slows gut motility, reduces tumor necrosis factor (TNF) concentrations [36], may improve fatigue and is the only antidepressant that improves sexual function [37].Clinically, our findings support the use of antidepressants in IBD but emphasize more the need for larger, powered clinical trials.Such trials should recruit patients with clinical depression according to diagnostic criteria and include patients in-and out of IBD remission.Trials could target a subgroup of patients, such as those with clinical depression and pain, for whom SNRIs may be particularly beneficial.Bupropion and mirtazapine are particularly promising, based on their pharmacology and clinical effects in other populations.Trials should also be powered to test the moderators and mediators of any improvement in depressive symptoms, such as improvement in IBD symptoms or immune parameters.
Our findings have several limitations.All included studies were modest in size.A number of studies did not specifically select participants with baseline depression or anxiety, despite this being the target population.Trials typically excluded patients with active IBD, which may be a missed opportunity to restore disordered gut-brain interaction.

Conclusion
Antidepressants show overall benefit for depressive symptoms and quality of life in IBD compared to placebo.SNRI antidepressants, such as duloxetine and venlafaxine, show particular benefit and additional improvement in anxiety.These findings, however, are based on a small number of studies with modest sample sizes.Large, placebo-controlled randomized trials of antidepressants in IBD are now needed.the manuscript for important intellectual content.C.D.M. codesigned the study, performed statistical analyses and revised the manuscript for important intellectual content.
All data supporting the authors' results and conclusions are presented in the manuscript.

Fig. 2 .
Fig. 2. Forest plots showing posttreatment differences between antidepressants and placebo in depressive symptoms (a), anxiety symptoms (b) and quality of life (c).

Fig. 3 .
Fig. 3. Forest plots showing posttreatment differences between antidepressants and placebo in depression symptoms (a), anxiety symptoms (b) and quality of life (c) stratified by subclass of antidepressant.
. Our findings, therefore, advance the literature by showing that antidepressants are more effective in IBD when meta-analysing based on RCTs.

Table 2 .
Summary of study results and outcomes for IBD papers , brief behavioural treatment of sleep in IBD; CDAI, Crohn's disease activity index; IBD, inflammatory bowel disease; IBDQ, IBD quality of life questionnaire; MCDAI, Mayo clinic disease activity index; SE, standard error; SF-36, short form 36 questionnaire; WHOQOL, WHO quality of life index; WHOQOL-BREF, WHO quality of life index -short version.

Table 3 .
CCDAN (Moncrieff et al., 2001)score for all included randomized and nonrandomized controlled trials

Table 4 .
NOS(Wells et al., 2022) score for all included cohort studies